Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice.
Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice.
复制标题
DOI：
10.1038/nm.4145
复制
发表时间：
2016-09
期刊：
影响因子：
82.9
通讯作者：
Ozcan U
中科院分区：
文献类型：
--
作者：
Lee J;Liu J;Feng X;Salazar Hernández MA;Mucka P;Ibi D;Choi JW;Ozcan U
肥胖及其相关疾病的全球患病率不断增加，迫切需要开发新的有效的治疗策略，以诱导健康的体重减轻。肥胖的特征是高瘦素血症和中枢瘦素抵抗。为了鉴定能够逆转瘦素抵抗从而促进体重减轻的化合物，我们分析了一个小分子文库，其mRNA表达谱与雷公藤红素类似，雷公藤红素是一种我们先前鉴定为瘦素敏化剂的天然化合物。通过这个过程，我们确定了另一种天然化合物，醉茄素A，也作为瘦素敏化剂。我们发现，对饮食诱导的肥胖小鼠进行醉茄素A治疗导致体重减轻20-25%，同时还减少了肥胖相关的异常，包括肝脂肪变性。Withaferin A轻微影响ob/ob和db/db小鼠的体重，这两种小鼠都缺乏瘦素信号传导。此外，与雷公藤红素不同，醉茄素A对葡萄糖代谢具有独立于其瘦素致敏作用的有益作用。我们的研究结果表明，饮食诱导的肥胖症的代谢异常，可以减轻动物内源性瘦素的敏感性，并表明醉茄素A是一个潜在的瘦素敏化剂与额外的抗糖尿病行动。
The increasing global prevalence of obesity and its associated disorders point to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules with mRNA expression profiles similar to that of celastrol, a naturally-occurring compound we previously identified as a leptin sensitizer. By this process we identified another natural compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin A treatment of diet-induced obese mice resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities including hepatic steatosis. Withaferin A marginally affects the body weight of ob/ob and db/db mice, which are both deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism independently from its leptin-sensitizing effect. Our results show that the metabolic abnormalities of diet-induced obesity can be mitigated by sensitizing animals to endogenous leptin, and indicate that withaferin A is a potential leptin sensitizer with additional anti-diabetic actions.
登录
查看更多内容
影响因子：
29
作者：
Ma, Xinran;Xu, Lingyan;Mueller, Elisabetta
通讯作者：
Mueller, Elisabetta
影响因子：
4.8
作者：
Kaileh, Mary;Vanden Berghe, Wim;Haegeman, Guy
通讯作者：
Haegeman, Guy
影响因子：
4.8
作者：
Harris, RBS;Kelso, EW;Grill, HJ
通讯作者：
Grill, HJ
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
64.5
作者：
Dietrich MO;Liu ZW;Horvath TL
通讯作者：
Horvath TL